This is a proposal to study CNS structure and function in mice homozygous for a knock-in allele[unreadable] (PolgAmut/PolgAmut) encoding a proof-reading-deficient mitochondrial DNA polymerase. These mutant[unreadable] mice, denoted mtDNA mutator mice, accumulate elevated levels of somatic mtDNA mutations, which cause[unreadable] a progressive respiratory chain dysfunction and multiple signs of premature aging. Sequencing has[unreadable] established that somatic mtDNA levels are also elevated in the CNS of mtDNA mutator mice and preliminary[unreadable] data presented in this proposal show that these mutations cause wide-spread focal cytochrome c oxidase[unreadable] (COX) deficiency in the brain. Up to now, there have been no detailed studies of the brains of these animals.[unreadable] We propose characterizing central nervous system structures and function of mtDNA mutator and wildtype[unreadable] (wt) littermate mice at several different ages (3, 6 and 10 months). The wt mice will also be studied at 18[unreadable] and 24 months of age.[unreadable] Once characterization of the CNS phenotype is completed, we propose to study the influence of treatment[unreadable] with antioxidant drugs as described in Project 1 and in collaboration with Dr. Bickford. In addition to CNS[unreadable] effects, we will also examine actions of these antioxidant drugs on the peripheral somatic changes in mt[unreadable] DNA mutator mice and wt controls.[unreadable] In subsequent studies, in collaboration with Project 3, we propose to study crosses of mt DNA mutator mice[unreadable] and wt controls with APP+PS1 mice. One aspect of Alzheimer's Disease (AD) that is not observed in current[unreadable] mouse models of AD is a loss of neurons. We predict that the combination of accumulation of mtDNA[unreadable] mutations observed in our mice with the mutant APP/PS1 expressed in the AD studied in Project 3 will result[unreadable] in neuronal loss. The hypothesis to be tested is that mitochondrial dysfunction predisposes to alzheimertype[unreadable] neuropathology and behavior disturbances. These experiments will test the hypothesis using genetic[unreadable] methods by determining if the mutator genotype causes aggravation and/or earlier onset of the APP+PS1[unreadable] phenotype.